3/1/2023 0 Comments Insurmountable antagonism![]() However, in contrast to candesartan, the responses to angiotensin II rapidly returned towards baseline values during the washout period. Irbesartan, losartan and EXP-3174 also blocked the angiotensin II-mediated contraction. ![]() This effect of candesartan was independent of drug concentration and exposure time prior to washing. Candesartan produced a long-lasting blockade of the vascular contractile response to angiotensin II, as shown by maintenance of inhibition during the washout period. Drug exposure was followed by washing for up to 2 h. The contractile response to repeated administration of angiotensin II was recorded before, during and following exposure (for 30-180 min) to candesartan, 0.1-1 nmol/l, irbesartan, 1-50 nmol/l, losartan, 30-100 nmol/l, and EXP-3174, 1-10 nmol/l. The contractile tension developed by the vascular smooth muscles was monitored using a force-displacement transducer. The portal vein preparation was pre-stretched to a passive force of 5 mN in an organ bath filled with oxygenated Krebs' buffer at 37☌. The contractile response to angiotensin II was studied in the isolated portal vein of the rat, during incubation with AT1-receptor blockers and after an extensive washout period. The purpose of this study was to compare the duration of angiotensin II antagonism by the AT 1 -receptor blockers candesartan, irbesartan, losartan and its active metabolite EXP-3174 in an isolated tissue preparation. It displays insurmountable antagonism of angiotensin II responses, binding tightly to and dissociating slowly from the AT 1 -receptor. The nature of these differences is yet to be elucidated.Candesartan is a new angiotensin II type 1 (AT 1 ) receptor blocker. In summary, the results reveal that these antagonists are insurmountable in nature against C5a for C5aR on at least two human cell types, and the differences in relative receptor binding affinities and antagonistic potencies against C5a are consistent with differences in receptors within these cell types. ![]() This trend was also reflected in their relative binding affinities, both antagonists having similar affinities (-logIC50 values) for C5aR in umbilical artery membranes (F-, 7.00 ± 0.46 MeFKPdChaWr, 7.23 ± 0.17), whereas in PMN membranes the C5aR affinity of the cycle F- (7.05 ± 0.06) was four times higher than that of acyclic MeFKPdChaWr (6.43 ± 0.24, P <0.05). There were differences in selectivities for the C5aR with F- (pK(b) 8.64 ± 0.21) being 30 times more potent than MeFKPdChaWr (pK(b) 7.16 ± 0.11, P <0.05) in PMNs, but of similar potency (pK(b) 8.19 ± 0.38 vs pK(b) 8.28 ± 0.29, respectively) in umbilical artery. ![]() In both PMNs and umbilical artery, the cyclic and acyclic C5a antagonists displayed insurmountable antagonism against C5a. We also compared their inhibition of myeloperoxidase (MPO) secretion from human PMNs and their inhibition of human umbilical artery contraction induced by human recombinant C5a. ![]() In this study we compared a new cyclic antagonist, F-, with an acyclic derivative, MeFKPdChaWr, for their capacities to bind to C5aR on human PMN and human umbilical artery membranes. Potent and highly selective small molecule antagonists have recently been developed by us for C5a receptors (C5aR) on human polymorphonuclear leukocytes (PMN). ![]()
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